Project Summary SCN8A, which encodes the voltage-gated sodium channel Nav1.6, is broadly expressed throughout the brain. The first SCN8A-associated epilepsy mutation was recently identified in 2012, and since then, an increasing number of de novo SCN8A mutations have been identified in patients with severe, refractory, childhood epilepsy. De novo SCN8A mutations have also been found in patients with autism, intellectual disability and developmental delay but with less severe epilepsy or no seizures. To better understand the phenotypic spectrum associated with SCN8A dysfunction, we generated and characterized a knock-in mouse line expressing the human SCN8A R1620L mutation which was identified in a patient with autism. Scn8aRL/+ mutants exhibit increased seizure susceptibility, spontaneous seizures, and behavioral deficits including social and cognitive impairment. A major challenge in the treatment of patients with SCN8A-associated disease is the broad range of clinical presentations. Furthermore, in many cases, behavioral comorbidities are not the primary treatment focus, and often persist or worsen, even if seizure control is obtained. Therefore, the goal of this proposal is to use the Scn8aR1620L/+ mutants to thoroughly and systematically compare the ability of 5 different antiepileptic drugs to improve both seizure and behavioral phenotypes.